Melanoma response to anti-PD-L1 immunotherapy requires JAK1 signaling, but not JAK2

Luo, Na; Formisano, Luigi; Gonzalez-Ericsson, Paula I.; Sánchez, Violeta; Dean, Phillip T.; Opalenik, Susan R.; Sanders, Melinda E.; Cook, Rebecca S.; Arteaga, Carlos L.; Johnson, Douglas B.; Balko, Justin M.

doi:10.1080/2162402x.2018.1438106

Cited by 62 publications

(51 citation statements)

References 41 publications

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“…In agreement with previous reports, ruxolitinib treatment diminished tumor infiltrating CD8 + and CD4 + T cells and significantly lowered NK cell numbers but did not result in tumor metastasis, even in the absence of p53 . In agreement with others, JAK inhibition abrogated interferon‐γ‐mediated STAT1 signaling and reduced PD‐L1 expression levels . Nevertheless, NK and CD8 + T cell activation markers were reduced in lungs of ruxolitinib treated mice.…”

Section: Discussionsupporting

confidence: 92%

“…17,18,42 In agreement with others, JAK inhibition abrogated interferon-γ-mediated STAT1 signaling and reduced PD-L1 expression levels. 43 Nevertheless, NK and CD8 + T cell activation markers were reduced in lungs of ruxolitinib treated mice. Furthermore, ruxolitinib elevated numbers of tumor infiltrating CD4 + IL17A + Th17 and CD4 + Foxp3 + regulatory T cells.…”

Section: Discussionmentioning

confidence: 98%

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JAK–STAT inhibition impairs K‐RAS‐driven lung adenocarcinoma progression

Mohrherr

Haber

Breitenecker

et al. 2019

Intl Journal of Cancer

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Oncogenic K‐RAS has been difficult to target and currently there is no K‐RAS‐based targeted therapy available for patients suffering from K‐RAS‐driven lung adenocarcinoma (AC). Alternatively, targeting K‐RAS‐downstream effectors, K‐RAS‐cooperating signaling pathways or cancer hallmarks, such as tumor‐promoting inflammation, has been shown to be a promising therapeutic strategy. Since the JAK–STAT pathway is considered to be a central player in inflammation‐mediated tumorigenesis, we investigated here the implication of JAK–STAT signaling and the therapeutic potential of JAK1/2 inhibition in K‐RAS‐driven lung AC. Our data showed that JAK1 and JAK2 are activated in human lung AC and that increased activation of JAK–STAT signaling correlated with disease progression and K‐RAS activity in human lung AC. Accordingly, administration of the JAK1/2 selective tyrosine kinase inhibitor ruxolitinib reduced proliferation of tumor cells and effectively reduced tumor progression in immunodeficient and immunocompetent mouse models of K‐RAS‐driven lung AC. Notably, JAK1/2 inhibition led to the establishment of an antitumorigenic tumor microenvironment, characterized by decreased levels of tumor‐promoting chemokines and cytokines and reduced numbers of infiltrating myeloid derived suppressor cells, thereby impairing tumor growth. Taken together, we identified JAK1/2 inhibition as promising therapy for K‐RAS‐driven lung AC.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 98%

JAK–STAT inhibition impairs K‐RAS‐driven lung adenocarcinoma progression

Mohrherr

Haber

Breitenecker

et al. 2019

Intl Journal of Cancer

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“…Because JAK/ STAT up-regulates the expression of PD-L1, it also plays an important role in tumor antigen expression. JAK1 is essential for both IFN-γ-mediated immune responses and MHCI/II expression, whereas JAK2 contributes to IFN-γ-induced STAT5 phosphorylation and PD-L1 expression, and mutations disrupt antigen presentation [122]. In addition to the JAK/STAT pathway, other factors cause changes in PD-L1 expression.…”

Section: Resistance Caused By Changes In Pd-l1 Expressionmentioning

confidence: 99%

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

et al. 2020

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Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

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“…In 2017, Shin et al [ 90 ] suggested that the presence of JAK1/2 LoF mutations can be a biomarker for resistance to PD-L1 therapy and that patients whose tumors exhibit such mutations would be poor candidates for ICB. Additionally, Luo et al [ 94 ] recently reported that JAK1 plays a more indispensable role than JAK2 in IFNγ-induced expression of MHC and PD-L1. Though few specific actionable JAK-STAT variants have been pinpointed, it is clear that any major alterations to this pathway are likely to affect responses to PD-(L)1 and CTLA-4 blockade.…”

Section: Immune-related Pathways Involved In Response and Resistancementioning

confidence: 99%

Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine

et al. 2018

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Immune checkpoint blockade (ICB) therapies, which potentiate the body’s natural immune response against tumor cells, have shown immense promise in the treatment of various cancers. Currently, tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are the primary biomarkers evaluated for clinical management of cancer patients across histologies. However, the wide range of responses has demonstrated that the specific molecular and genetic characteristics of each patient’s tumor and immune system must be considered to maximize treatment efficacy. Here, we review the various biological pathways and emerging biomarkers implicated in response to PD-(L)1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) therapies, including oncogenic signaling pathways, human leukocyte antigen (HLA) variability, mutation and neoantigen burden, microbiome composition, endogenous retroviruses (ERV), and deficiencies in chromatin remodeling and DNA damage repair (DDR) machinery. We also discuss several mechanisms that have been observed to confer resistance to ICB, such as loss of phosphatase and tensin homolog (PTEN), loss of major histocompatibility complex (MHC) I/II expression, and activation of the indoleamine 2,3-dioxygenase 1 (IDO1) and transforming growth factor beta (TGFβ) pathways. Clinical trials testing the combination of PD-(L)1 or CTLA-4 blockade with molecular mediators of these pathways are becoming more common and may hold promise for improving treatment efficacy and response. Ultimately, some of the genes and molecular mechanisms highlighted in this review may serve as novel biological targets or therapeutic vulnerabilities to improve clinical outcomes in patients.

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Melanoma response to anti-PD-L1 immunotherapy requires JAK1 signaling, but not JAK2

Cited by 62 publications

References 41 publications

JAK–STAT inhibition impairs K‐RAS‐driven lung adenocarcinoma progression

JAK–STAT inhibition impairs K‐RAS‐driven lung adenocarcinoma progression

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine

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